Antibody with infinite affinity for in vivo tracking of genetically engineered lymphocytes Journal Article

Authors: Krebs, S.; Ahad, A.; Carter, L. M.; Eyquem, J.; Brand, C.; Bell, M.; Ponomarev, V.; Reiner, T.; Meares, C. F.; Gottschalk, S.; Sadelain, M.; Larson, S. M.; Weber, W. A.
Article Title: Antibody with infinite affinity for in vivo tracking of genetically engineered lymphocytes
Abstract: There remains an urgent need for the noninvasive tracking of transfused chimeric antigen receptor (CAR) T cells to determine their biodistribution, viability, expansion, and antitumor functionality. DOTA antibody reporter 1 (DAbR1) comprises a single-chain fragment of the antilanthanoid-DOTA antibody 2D12.5/G54C fused to the human CD4-transmembrane domain and binds irreversibly to lantha-noid (S)-2-(4-acrylamidobenzyl)-DOTA (AABD). The aim of this study was to investigate whether DAbR1 can be expressed on lymphocytes and used as a reporter gene as well as a suicide gene for therapy of immune-related adverse effects. Methods: DAbR1 was subcloned together with green fluorescent protein into an SFG-retroviral vector and used to transduce CD3/CD28-activated primary human T cells and second-generation 1928z (CAR) T cells. Cell surface expression of DAbR1 was confirmed by cell uptake studies with radiolabeled AABD. In addition, the feasibility of imaging of DAbR1-positive T cells in vivo after intravenous injection of86Y/177Lu-AABD was studied and radiation doses determined. Results: A panel of DAbR1-expressing T cells and CAR T cells exhibited greater than 8-fold increased uptake of86Y-AABD in vitro when compared with nontransduced cells. Imaging studies showed86Y-AABD was retained by DAbR1-positive T cells while it continuously cleared from normal tissues, allowing for in vivo tracking of intravenously administered CAR T cells. Normal-organ dose estimates were favorable for repeated PET/CT studies. Selective T cell ablation in vivo with177Lu-AABD seems feasible for clustered T-cell populations. Conclusion: We have demonstrated for the first time that T cells can be modified with DAbR1, enabling their in vivo tracking via PET and SPECT. The favorable biodistribution and high image contrast observed warrant further studies of this new reporter gene. COPYRIGHT © 2018 by the Society of Nuclear Medicine and Molecular Imaging.
Keywords: pet imaging; lymphocytes; car t cells; dota antibody reporter gene
Journal Title: Journal of Nuclear Medicine
Volume: 59
Issue: 12
ISSN: 0161-5505
Publisher: Society of Nuclear Medicine  
Date Published: 2018-12-01
Start Page: 1894
End Page: 1900
Language: English
DOI: 10.2967/jnumed.118.208041
PROVIDER: scopus
PMCID: PMC6278895
PUBMED: 29903928
Notes: J. Nucl. Med. -- Cited By :1 -- Export Date: 2 January 2019 -- Article -- CODEN: JNMEA -- Source: Scopus
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MSK Authors
  1. Michel W J Sadelain
    449 Sadelain
  2. Steven M Larson
    736 Larson
  3. Thomas Reiner
    70 Reiner
  4. Wolfgang Andreas Weber
    145 Weber
  5. Christian Brand
    19 Brand
  6. Justin Gabriel Andre Francois Eyquem
    13 Eyquem
  7. Simone Susanne Krebs
    12 Krebs
  8. Afruja Ahad
    4 Ahad
  9. Meghan Bell
    3 Bell
  10. Lukas M Carter
    6 Carter